Medical endoprosthesis or implants for a wide variety of applications are known from the state of the art in great diversity. Implants as defined by the present invention are endovascular prostheses or other endoprostheses, for example stents, fastening elements for bones, such as screws, plates or nails, surgical suture material, intestinal clamps, vascular clips, prostheses in the area of hard and soft tissues, such as anchoring elements for electrodes, particularly for pacemakers or defibrillators.
These days, stents that are used for the treatment of stenoses (vascular constrictions) are employed especially frequently as implants. They have a body in the form of a tubular or hollow-cylindrical base mesh, which is open at both longitudinal ends. The tubular base mesh of such an endoprosthesis is inserted into the vessel requiring treatment and is intended to support the vessel. Stents have become established in particular for the treatment of vascular diseases. Constricted areas in the vessels can be dilated through the use of stents, resulting in increased lumen. While through the use of stents or other implants, an optimal vascular cross-section can be achieved, which is primarily necessary for successful treatment, the lasting presence of such a foreign object triggers a cascade of microbiological processes, which may result in gradual blockage of the stent and, in the worst case, in vascular obliteration.
One approach to solve this problem is to produce the stent or other implants from a biodegradable material.
Biodegradation refers to hydrolytic, enzymatic and other metabolic decomposition processes in the living organism, which are caused primarily by the body fluids coming in contact with the biodegradable material of the implant and result in a gradual dissolution of the structures of the implant containing the biodegradable material. This process causes the implant to lose the mechanical integrity thereof at some point. A term that is frequently used synonymously with biodegradation is biocorrosion. The term bioresorption encompasses the subsequent resorption of the decomposition products by the living organism.
Materials that are suitable for the body of biodegradable implants may comprise polymers or metals, for example. The body can be produced from several of these materials. The common characteristic of these materials is the biodegradability thereof. Examples of suitable polymer compounds include polymers from the group consisting of cellulose, collagen, albumin, casein, polysaccharides (PSAC), polylactide (PLA), poly-L-lactide (PLLA), polyglycol (PGA), poly-D,L-lactide-co-glycolide (PDLLA-PGA), polyhydroxybutyric acid (PHB), polyhydroxyvaleric acid (PHV), polyalkyl carbonates, polyorthoesters, polyethylene terephtalate (PET), polymalonic acid (PML), polyanhydrides, polyphosphazenes, polyamino acids and the copolymers thereof, as well as hyaluronic acid. Depending on the desired properties, the polymers may be present in pure form, in derivatized form, in the form of blends or as copolymers. The present invention relates to implants comprising a metallic biodegradable material that is based on magnesium or magnesium alloys.
Stents comprising coatings that have various functions are already known. Such coatings are used, for example, to release medication, to arrange an X-ray marker, or to protect the subjacent structures.
In the implementation of biodegradable implants, the degradability is to be controlled in accordance with the desired therapy and/or use of the respective implant (coronary, intracranial, renal, etc.). For many therapeutic applications, for example, an important target corridor is that the implant loses the integrity thereof within a period of four weeks to six months. Integrity, that is mechanical integrity, shall be understood as the property whereby the implant suffers hardly any mechanical losses in comparison with the non-degraded implant. This means that the implant still has enough mechanical stability that the collapse pressure, for example, has decreased only slightly, that is, to no less than 80% of the nominal value. If the integrity thereof is preserved, the implant can thus still perform the primary function thereof, which is to keep the vessel open. As an alternative, the integrity can be defined in that the implant is still mechanically so stable that it is hardly subject to any geometric changes in the loaded state thereof in the vessel; for example, it does not slump significantly, which is to say, it still has at least 80% of the dilation diameter under load or, in the case of a stent, hardly any of the supporting struts are broken.
Biodegradable magnesium implants, in particular magnesium stents, have proven to be particularly promising for the stated target corridor of degradation, however not only do they lose the mechanical integrity and/or supporting effect thereof too early, the loss of integrity also fluctuates greatly in vitro and in vivo. This means that, in the case of magnesium stents, the collapse pressure declines too rapidly over time and/or the reduction in the collapse pressure exhibits excessive variability and therefore cannot be sufficiently determined.
Various mechanisms of controlling the degradation of magnesium implants have already been described in the prior art. They are based, for example, on organic and inorganic protective layers or combinations thereof, which provide resistance to the human corrosion environment and the corrosion processes taking place there. Existing solutions are characterized in that barrier layer effects are achieved, which are based on a spatial separation, preferably free of defects, between the corrosion medium and the metallic material, in particular the metallic magnesium. The protection from degradation is safeguarded by protective layers having various compositions and by defined geometric distances (diffusion barriers) between the corrosion medium and the magnesium base material. Other solutions are based on alloying constituents of the biodegradable material of the implant body, which influence the corrosion process by displacement of the layer in the electrochemical series. Other solutions in the field of controlled degradation induce predetermined breaking effects by applying physical changes (such as local cross-sectional changes) and/or chemical changes in the stent surface (such as multilayers having different chemical compositions locally). However, the solutions described above usually fail to ensure that the dissolution that occurs as a result of the degradation process, and the resulting breakage of the stents, take place in the required time window. The result is that degradation of the implant begins either too early or too late or the variability in the degradation is excessive.
A further problem encountered in connection with coatings is that stents or other implants usually assume two states, namely a compressed state having a small diameter and an expanded state having a larger diameter. In the compressed state, the implant can be inserted into the blood vessel to be supported by means of a catheter and positioned at the site to be treated. At the site of treatment, the implant is then dilated by means of a balloon catheter, for example. Because of this change in diameter, the body of the implant is exposed to mechanical stress. Additional mechanical stresses on the implant may occur during production or movement of the implant in or with the vessel in which the implant is inserted. With the known coatings, this results in the disadvantage that the coating cracks during the deformation of the implant (such as the formation of microcracks) or is removed in some regions. This may result in an unspecified local degradation. Furthermore, the onset and the speed of the degradation depend on the size and distribution of the microcracks, which form due to deformation and are imperfections that are difficult to monitor. This results in wide variations of the degradation times.
A medical device, such as a catheter or stent, is known from the documents US 2008/0086195 A1 and WO 2008/045184 A1, wherein a polymer-free coating is applied by way of a plasma electrolytic process (plasma electrolytic deposition, PED). The plasma electrolytic coating is used to introduce additional active ingredients containing a medication or a therapeutic agent into the coating. The plasma electrolytic coating comprises plasma electrolytic oxidation (PEO), micro-arc oxidation (MAO), plasma-arc oxidation (PAO), anodic spark oxidation, and plasma electrolytic saturation (PES). The plasma electrolytic coating is carried out by using alternating voltage. The plasma electrolytic treatment includes the use of various electric potentials between the medical device and a counter-electrode, which generates an electric discharge (a spark discharge or a micro-arc plasma micro discharge) at or in the vicinity of the surface of the medical device, which does not bring about any significant extension in the degradation times. The method provided in these publications thus does not solve the problem stated above.
An implant and a method for producing an implant are known from the document DE 10 2008 042 602, wherein a body made of metallic material is subjected to a plasmachemical treatment. Due to the plasmachemical treatment, a layer, which comprises phosphates, hydroxides and oxides of the metallic material, strontium carbonate or strontium phosphate, is generated on the body surface with a frequency of at least 1 kHz. While the plasmachemical treatment generates a protective layer on the surface of the implant, which prevents degradation for a while, it has meanwhile been found that a significant increase in the service life of such an implant cannot be achieved in this way.